Devices, systems, and methods for pulmonary arterial hypertension (pah) assessment and treatment

ABSTRACT

Provided herein are devices, systems, and methods for assessing, treating, and for developing new treatments for pulmonary arterial hypertension (PAH) using pulmonary artery pressure (PAP) values and/or cardiac output (CO) estimates.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a continuation application of, and claimspriority to U.S. application Ser. No. 14/086,478, filed Nov. 21, 2013which claims benefit of U.S. Provisional Application No. 61/728,913,filed Nov. 21, 2012, and U.S. Provisional Application No. 61/799,536,filed Mar. 15, 2013, each of which are hereby incorporated herein byreference in their entirety.

TECHNICAL FIELD

This application generally relates to devices, systems, and methods forthe assessment and treatment of pulmonary arterial hypertension (PAH).

BACKGROUND

Pulmonary arterial hypertension (PAH) is a progressive disease thatresults in elevation of the pulmonary artery pressure and ultimatelydevelopment of right ventricular failure. Baseline and periodic invasivehemodynamics via right heart catheterization are generally obtained inorder to characterize and follow the extent of hemodynamic derangement,response to therapy, and as an end point in clinical trials of noveltherapy.

SUMMARY

Provided herein are methods for assessing, treating, and for developingnew treatments for PAH.

For example, provided are methods for evaluating progress of pulmonaryarterial hypertension (PAH) in a subject, or an outcome in a subjecthaving PAH. Example methods include obtaining a pulmonary arterypressure waveform from the subject. One or more pulmonary arterypressure (PAP) values are determined from the pulmonary artery waveform.Cardiac output (CO) is estimated using the pulmonary artery pressurewaveform. One or more of the PAP values and one or more of the COestimates are compared to standard PAP and CO values respectively. Thecomparisons of PAP and CO are used to monitor the PAH progression oroutcome in the subject.

An agent can be administered to the subject, and determined PAP valuesand estimated CO values, in combination, can be used for evaluatingtreatment of a subject having PAH. In this regard, an example methodincludes administering an agent to the subject and obtaining a pulmonaryartery pressure waveform from the subject. One or more pulmonary arterypressure (PAP) values are determined from the pulmonary artery waveform.Cardiac output (CO) is estimated using the pulmonary artery pressurewaveform. One or more of the PAP values and one or more of the COestimates are compared to standard PAP and CO values respectively, forexample, to determine trends in PAP values and CO estimates in thesubject. The comparisons of PAP and CO, for example trends, are used tomonitor the effect of the administered agent on the PAH condition in thesubject.

Additional methods for evaluating treatment of a subject having PAHinclude administering an agent to the subject and obtaining a pulmonaryartery pressure waveform from the subject. One or more pulmonary arterypressure (PAP) values are determined from the pulmonary artery waveformand are compared to a standard PAP value. The comparison of PAP is usedto monitor the effect of the administered agent on the PAH condition inthe subject. A decrease in the one or more determined PAP valuescompared to the PAP standard, for example a decreasing trend in thesubject's PAP values, indicates a beneficial effect of the administeredagent on the PAH condition in the subject. An increase in the one ormore determined PAP values compared to the PAP standard, for example anincreasing trend in the subject's PAP values, indicates no beneficialeffect of the administered agent on the PAH condition in the subject.

Additional methods for evaluating treatment of a subject having PAHinclude administering an agent to the subject and obtaining a pulmonaryartery pressure waveform from the subject. Cardiac output (CO) isestimated using the pulmonary artery pressure waveform and compared to astandard CO value. The comparison of CO is used to monitor the effect ofthe administered agent on the PAH condition in the subject. In thismethod, an increase in the one or more estimated CO values compared tothe CO standard, for example an increasing trend in the subject's COestimates, indicates a beneficial effect of the administered agent onthe PAH condition in the subject. A decrease in the one or moreestimated CO values compared to the CO standard, for example adecreasing trend in the subject's CO estimated values, indicates nobeneficial effect of the administered agent on the PAH condition in thesubject.

Optionally, the standard PAP value in the methods described herein isone or more previously determined PAP values from the subject. Forexample, the standard is optionally a PAP value determined by obtaininga pulmonary artery pressure waveform from the subject and using thatwaveform to determine the PAP value. In this way, trends in PAP valuesin the subject can be monitored. These trends are optionally used tomonitor PAH progression or outcome in the subject.

For example, a lowering trend in PAP values over time in, optionally, asubject having PAH, indicates improvement in the PAH condition. This canalso optionally indicate improved outcome in the subject, such as, forexample, reduced hospitalizations, lower mortality, or lower morbidity.

The trends of PAP are optionally combined with the determination andmonitoring of trends in CO in the subject to evaluate the progress ofPAH in the subject. For example, the standard CO value, which can beused to determine such trends, is optionally based on one or morepreviously estimated CO values from the subject, or established normalranges. A rising trend in CO estimates over time in, optionally, asubject having PAH, indicates improvement in the PAH condition. This canalso optionally indicate or predict improved outcome in the subject,such as, for example, reduced hospitalizations, lower mortality, lowermorbidity, or improved exercise tolerance. The standard PAP or CO valuecan also optionally be established normal hemodynamic values, such asPAP and/or CO values. Normal hemodynamic values include normal valuesfor a given subject or population.

The details of one or more embodiments are set forth in the accompanyingdrawings and the description below. Other features, objects, andadvantages will be apparent from the description and drawings, and fromthe claims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph showing monitoring of PAP in a subject with PAH priorto and subsequent to administration of therapy to the subject.

FIGS. 2A and 2B are graphs showing consistent and accurate COmeasurements using an implantable sensor as described herein.

FIG. 3 is a graph showing CO agreement with pressure changes.

FIG. 4 is a graph showing trends in CO, mPAP and TPR in a PAH subjectbefore and after administration of treatment agents.

FIG. 5 is a graph showing estimated Cardiac Output.

FIGS. 6A and 6B are graphs showing CO measurement Bland-Altman Agreementwith an implantable CardioMEMS® (Atlanta, Ga.) sensor versus a COreference standard.

FIG. 7 illustrates an exemplary system for communicating with a wirelesssensor implanted within a body.

DETAILED DESCRIPTION

Progressive right ventricular failure is a common consequence of PAH andis the leading cause of premature death. In the original NIH pulmonaryhypertension registry, a prognostic equation was developed that includedright atrial pressure, pulmonary artery pressure, and cardiac index.Right atrial pressure, cardiac index, and PAP were significant factorswith respect to outcome, listed in order of statistical importance.While RA pressure has a high correlation with outcomes, this is becauseit is a direct symptom of RV failure, which occurs in the latter stageof the disease progression when treatment options are limited, and RVfailure has a high correlation with outcomes. However, the diagnosticusefulness of this parameter in the earlier stages of the diseaseprogression is limited.

CO and PAP provide an indication of the ventricular stroke work, whichwhen elevated over extended timeframes, overloads the RV and accelerateRV failure. Calculated parameters such as Stroke Work (mPAP×StrokeVolume) and Total Pulmonary Resistance (TPR) (mPAP/CO) use PAP and COtogether to provide an assessment of the RV workload. Pulmonary arterypressure and pulmonary arterial pressure are used synonymouslythroughout.

Example inventions described herein are based on the use of PAP, CO, andother relevant metrics calculated from these parameters such as StrokeWork and TPR, alone or in combination, can be used to assess, treat, anddevelop new treatments for PAH and heart failure resulting from PAH. Theprovided methods are optionally used for evaluating progress ofpulmonary arterial hypertension (PAH) in a subject, or an outcome in asubject having PAH.

The methods described herein are optionally used to develop atherapeutic agent. The term “developing” or “development” as used hereinin reference to therapeutics are broad terms that include, by way ofexample and not limitation, prospective design, or selection, of one ormore potential therapeutic methods or compounds or retrospective studyof one or more therapeutic methods or compounds or design of studies ofsuch therapeutic methods or compounds. In this regard, to develop ordevelopment of a therapeutic can include, for example, changes to anactive ingredient or formulation and also includes, for example, studydesign for a therapeutic. Optionally, study design is for a clinicaltrial and development of a study design can include establishing trialmetrics or trial durations.

The methods described herein can also be used to identify a candidatetherapeutic agent for administration to a patient. All or a subset ofthe hemodynamic data, such as, for example, CO estimates and/or PAPvalues, can be correlated with the candidate therapeutic agent toindicate a predicted change in one or more hemodynamic values in thepatient that would result from administration of the candidate agent.The predicted change can be used to indicate the predicted effect of thecandidate agent on the hemodynamic parameter of the subject.

A change in one or more of the measured hemodynamic values, such as, forexample, CO estimates and/or PAP values resulting from theadministration of the therapeutic agent can be identified, the changeindicating an effect of the therapeutic agent on the hemodynamicparameter of the subject. Optionally, the hemodynamic data comprises atleast one hemodynamic value measured in a subject prior toadministration of the therapeutic agent. Optionally, the hemodynamicdata comprises at least one hemodynamic value measured in a subjectconcurrent with administration of the therapeutic agent. Optionally, thehemodynamic data comprises at least one hemodynamic value measured in asubject subsequent to administration of the therapeutic agent.Optionally, the hemodynamic data comprises at least one hemodynamicvalue measured in a subject prior to administration of the therapeuticagent and at least one hemodynamic value measured in a subjectsubsequent to administration of the therapeutic agent. In some aspects,one or more additional therapeutic agents are administered to thesubject prior to, concurrently with, or subsequent to the therapeuticagent.

Optionally, the therapeutic agent can be modified to increase theindicated effect. For example, if the indicated effect is desired, thestructure of the therapeutic agent can be modified to increase theindicated effect. The therapeutic agent can also be modified to decreasethe indicated effect. For example, if the indicated effect is notdesirable, then the structure of the therapeutic agent can be modifiedto decrease the indicated effect. Moreover, an administrationcharacteristic of the therapeutic agent can be modified to increase ordecrease the indicated effect.

The administration characteristic can be selected from the groupconsisting of dosage amount, number of doses, timing of doses, route ofadministration, and total dosage. When the indicated effect is to beincreased or decreased, one or more portions of the therapeutic agentresponsible for the indicated effect can be determined. Optionally, asecond therapeutic agent including the one or more portions of thetherapeutic agent responsible for the indicated effect can be designed.

The indicated effect can used to assess safety of the therapeutic agentfor administration to a mammal or population thereof. In some examples,the indicated effect is used to assess the toxicity of the therapeuticagent for administration to a mammal or population thereof. Optionally,the toxicity is cardiac toxicity. The indicated effect can also be usedto assess the efficacy of the therapeutic agent for administration to amammal or population thereof. And, the indicated effect can also be usedto predict the effect or effects of the therapeutic agent or agentshaving the same or similar pharmacological characteristics on thehemodynamic parameter. Optionally, the indicated effect is used topredict the effect or effects of the therapeutic agent or agents havingthe same or similar pharmacological characteristics on a hemodynamicparameter of a mammal. In some aspects, the indicated effect is used todetermine an end point for a clinical trial.

The described methods can further comprise determining one or morecharacteristics of the subject. The determined characteristic can be aphysical, physiologic, metabolic, chronological, disease state, drugadministration history, medical history, or genetic characteristic.

The characteristic can be correlated with the indicated effect in thesubject. The correlation of the characteristic and the indicated effectin the subject can be used to select one or more additional subjects foradministration of the therapeutic agent or for a therapeutic agenthaving the same or similar indicated effect. The correlation of thecharacteristic and the indicated effect can also be used to select oneor more additional subjects to participate in a clinical trial for thetherapeutic agent or for a therapeutic agent having the same or similarindicated effect.

These determinations can be used to facilitate development of atherapeutic by efficiently identifying preferred dosages that arecorrelated to improved physiological data for clinical trials. Thedeterminations can also be used for determining proper dosages ofcommercial products for general and specific populations of subjects.For example, the described methods can be used to arrive at dosinglevels based on patient/subject profiles including, but not limited to,pulmonary artery pressure response and/or cardiac output response to astudy or commercial drug or with other hemodynamic metrics alone or incombination with characteristics such as age, weight and concurrent drugadministration or drug-drug interaction. Example methods forfacilitating development of therapeutics include methods for evaluatingprogress or outcome in PAH subjects, and for evaluating treatment in PAHsubjects. These methods can also be used in clinical treatment andmanagement of subjects.

Example methods include obtaining a pulmonary artery pressure waveformfrom the subject. One or more pulmonary artery pressure (PAP) values aredetermined from the pulmonary artery waveform. Cardiac output (CO) isestimated using the pulmonary artery pressure waveform. One or more ofthe PAP values and one or more of the CO estimates are compared tostandard PAP and CO values respectively. The comparisons of PAP and COare used to monitor the PAH progression or outcome in the subject.

Optionally, the standard PAP value is one or more previously determinedPAP values from the subject. For example, the standard is optionally aPAP value determined by obtaining a pulmonary artery pressure waveformfrom the subject and using that wave form to determine the PAP value. Inthis way, trends in PAP values in the subject can be monitored. Thesetrends are optionally used to monitor PAH progression or outcome in thesubject.

For example, a lowering trend in PAP values over time in, optionally, asubject having PAH indicates improvement in the PAH condition. This canalso optionally indicate improved outcome in the subject, such as, forexample, reduced hospitalizations, lower mortality, or lower morbidity.

The trends of PAP are optionally combined with the determination andmonitoring of trends in CO in the subject to evaluate the progress ofPAH in the subject. For example, the standard CO value, which can beused to determine such trends, is optionally based on one or morepreviously estimated CO values from the subject.

The standard PAP value can also optionally be a clinically relevanttarget PAP value for the subject and the standard CO value canoptionally be a clinically relevant CO target value for the subject. Forexample, an optional clinical target standard is a PAP of about 25 mmHg.Optionally, the determined PAP value is less than 25 mmHg. Theclinically relevant target for either CO or PAP can be, for example,determined by a health care professional treating or managing the PAHsubject. A clinically relevant target value can be a value that is anormal value for the subject, or a population of which the subject is amember, or an improved value for the subject, goal value for thesubject, or any other value determined by a health care professionalmanaging the subject.

Optionally, one or more PAP values of the subject determined prior todetermining the PAP value from the obtained pulmonary artery pressurewaveform are greater than 25 mmHg. The clinically relevant target foreither CO or PAP can be, for example, determined by a health careprofessional treating or managing the PAH subject.

Thus, trends in PAP and CO can be monitored relative to previous valuesfrom the subject or to clinical target values that may optionally bedetermined by a health care professional treating or managing thesubject.

The trends can be used to determine if the subject is improving. Forexample, a decrease in the one or more PAP values compared to thestandard PAP value, combined with one or more increased or stable COestimates compared to the standard CO value can indicate or predictimprovement in the subject. In another example, one or more stable PAPvalues compared to the standard PAP value, combined with one or moreincreased CO estimates compared to the CO standard value indicates orpredicts improvement of the PAH in the subject.

Alternatively, a decrease in one or more CO estimates compared to thestandard CO value, combined with one or more increased or stable PAPvalues compared to the standard PAP value can indicate or predictworsening of the PAH in the subject. In another example, an increase inone or more PAP values compared to the standard PAP values, combinedwith a stable or decreased CO value compared to the standard CO valueindicates or predicts worsening of the PAH in the subject. Optionally,as described above, trends in PAP values and trends in CO value are usedtogether to monitor progress or to predict outcome in subjects havingPAH.

In other examples, however, PAP value trends or CO value trends are usedindependently to monitor progress or to predict outcomes in subjectshaving PAH.

For example, a method for evaluating treatment of a subject having PAHincludes administering an agent to the subject and obtaining a pulmonaryartery pressure waveform from the subject. One or more pulmonary arterypressure (PAP) values are determined from the pulmonary artery waveformand are compared to a standard PAP value. The comparison of PAP is usedto monitor the effect of the administered agent on the PAH condition inthe subject. In this way, trends in PAP values independent of CO valuesare used to evaluate treatment of the subject for the PAH condition. Adecrease in the one or more determined PAP values compared to the PAPstandard, for example a decreasing trend in the subject's PAP values,indicates a beneficial effect of the administered agent on the PAHcondition in the subject. An increase in the one or more determined PAPvalues compared to the PAP standard, for example an increasing trend inthe subject's PAP values, indicates no beneficial effect of theadministered agent on the PAH condition in the subject.

In regard to CO, independent of PAP, an example method for evaluatingtreatment of a subject having PAH includes administering an agent to thesubject and obtaining a pulmonary artery pressure waveform from thesubject. Cardiac output (CO) is estimated using the pulmonary arterypressure waveform and compared to a standard CO value. The comparison ofCO is used to monitor the effect of the administered agent on the PAHcondition in the subject. In this way, trends in estimated CO values,independent of PAP values, are used to evaluate treatment of the subjectfor the PAH condition. In this method, an increase in the one or moreestimated CO values compared to the CO standard, for example anincreasing trend in the subject's CO estimates, indicates a beneficialeffect of the administered agent on the PAH condition in the subject. Adecrease in the one or more estimated CO values compared to the COstandard, for example a decreasing trend in the subject's CO estimatedvalues, indicates no beneficial effect of the administered agent on thePAH condition in the subject.

In regard to use of determined PAP values and estimated CO values, incombination, for evaluating treatment of a subject having PAH, anexample method includes administering an agent to the subject andobtaining a pulmonary artery pressure waveform from the subject. One ormore pulmonary artery pressure (PAP) values are determined from thepulmonary artery waveform. Cardiac output (CO) is estimated using thepulmonary artery pressure waveform. One or more of the PAP values andone or more of the CO estimates are compared to standard PAP and COvalues respectively, for example to determine trends in PAP values andCO estimates in the subject. The comparisons of PAP and CO, for exampletrends, are used to monitor the effect of the administered agent on thePAH condition in the subject.

The trends can be used to determine the effect of the administered agenton the PAH condition in the subject. For example, a decrease in the oneor more PAP values compared to the standard PAP value, combined with oneor more increased or stable CO estimates compared to the standard COvalue can indicates a beneficial effect of the administered agent on thePAH condition in the subject. In another example, one or more stable PAPvalues compared to the standard PAP value, combined with one or moreincreased CO estimates compared to the CO standard value indicates abeneficial effect of the administered agent on the PAH condition in thesubject.

Alternatively, a decrease in one or more CO estimates compared to thestandard CO value, combined with one or more increased or stable PAPvalues compared to the standard PAP value can indicate no effect or adetrimental effect of the administered agent on the PAH condition in thesubject. In another example, an increase in one or more PAP valuescompared to the standard PAP values, combined with a stable or decreasedCO value compared to the standard CO value indicate no effect or adetrimental effect of the administered agent on the PAH condition in thesubject.

The PAP values and or CO estimates can also be used to derive a thirdvalue indicative of progression or treatment of PAH. In this regard, asused herein, use of PAP and or CO values and estimates includes use orother values derived from PAP and CO. Derived metrics include StrokeWork and TPR, alone or in combination, which are within the definitionof the use of CO and or PAP.

The administration of the pharmaceutical agent, for example, the agentadministered, dosage, timing, protocol, or the like, can be modified ormaintained after determining the effect of the agent of the PAHcondition in the subject. For example, administration of thepharmaceutical agent is optionally maintained at its current dosage andor dosing regimen when improvement is indicated. In another example, thepharmaceutical agent is changed, or the dosage or dosing regimenmodified when improvement is not indicated. In another example, theinformation obtained on PAP, CO, or both are used to determine aneffective dosage or administration protocol for the agent or to evaluatethe same, for example, in a clinical trial setting.

Therapeutic goals optionally include lowering or maintaining PAP and/orincrease or maintain CO. Additional therapeutic goals include reducingor maintaining PVR. Optionally CO is increased while PAP is reduced inthe subject. Optionally, CO or PAP is increased while PAP or CO ismaintained respectfully. TPR is used as a surrogate for PVR in thecontext of PAH. If the etiology of disease is understood by RHC to bePAH with minimal component of left heart disease, change TPR can then beused to infer changes in PVR.

In the described methods, the obtained pulmonary artery pressurewaveform is optionally obtained with a wireless sensor implanted in thesubject. In addition, one or more of the standard pulmonary arterypressure values are optionally determined from a pulmonary arterypressure waveform obtained with a wireless sensor implanted in thesubject. Therefore, the pulmonary artery pressure waveform is optionallyobtained wirelessly and the standard values can be determined from apulmonary artery waveform obtained wirelessly. In either case, thepulmonary artery pressure waveform is optionally obtained using animplanted sensor. Optionally, the implanted sensor is a pressure sensor,which is optionally implanted in the pulmonary artery of the subject.Optionally, the sensor lacks percutaneous connections. Optionally, thesensor is energized from an external source. Optionally, the sensor is apassive sensor energized to return pressure readings by anelectromagnetic field.

Because of the nature of the sensors described above, the pulmonaryartery pressure waveform is optionally obtained outside of a typicalclinical evaluation environment. For example, the pulmonary arterywaveform is optionally obtained while the subject is exercising.Exercising includes any activity of the subject. For example, exerciseor exercising includes activities of daily living, prescribed exercise,walking, biking, running or the like. Optionally, the pulmonary arterypressure waveform is obtained while the subject is asleep.

An effective system and sensor for measurement of cardiovascularphysiology information, such as obtaining the pulmonary artery pressurewaveform is the CARDIOMEMS (Atlanta, Ga.) heart sensor. As described byU.S. Pat. No. 7,699,059 entitled “Implantable Wireless Sensor” and U.S.Pat. No. 7,679,355 entitled “Communicating with an Implanted WirelessSensor,” these sensors are MEMS-based sensors that are implanted in thepulmonary artery, more particularly in the distal pulmonary arterybranch and are configured to be energized with RF energy to returnhigh-frequency, high-fidelity dynamic pressure information from aprecisely-selected location within a patient's body.

The sensors are optionally used to generate a real-time or substantiallyreal-time pressure waveform. Via signal acquisition and processingtechniques, a pressure waveform is optionally generated via a processorcoupled with memory that contains the appropriate algorithm to relatethe electrical characteristics of the circuit to the pressure of the PA.

In parallel or via discrete processors and memory elements, subsequentprocessing of the pressure waveform is performed. Summary values foreach reading optionally include systolic PAP, diastolic PAP, mean PAP,heart rate, and estimated cardiac output.

PAP values are optionally determined by analysis of the pressurewaveform to determine the average maximum waveform values for systolicPAP, average minimum waveform values for diastolic PAP, and average ofall waveform values for mean PAP.

Heart Rate is optionally determined in the following manner: The timingof repetitive relevant hemodynamic events within the cardiac cycle, suchas optionally the average time interval between consecutive systolic ordiastolic pressure values, is used to determine the average timeinterval between beats. The average time interval between beats isoptionally used to determine the average heart rate as 60(s/min.)/average time interval between beats (s/beat) to determine theaverage heart rate in beats per minute.

Cardiac Output (CO) is estimated based on the pulmonary arterialpressure waveform using the following approach. For each cardiac cycle,the pulmonary arterial pressure waveform P(t), comprised of an array ofconsecutive discrete paired pressure (p) and time (t) values,P(t)={(p₁,t₁), (p₂,t₂) . . . }, is optionally analyzed to identify thefollowing relevant reference pressure and time points for each beat:

-   -   P1,T1 pressure and time at start of systole and end of diastole.    -   P2,T2 pressure and time at end of the RV incident wave/beginning        of reflected wave indicated as first upslope pressure incisura        after the systolic upslope dP/dT max or alternatively at the        maximum of the pressure beat.    -   P3,T3 pressure and time at end of systole/end of outflow        demarcated by the dicrotic notch/pulmonic valve closure.

Optionally the pressure waveform features associated with the RVincident pressure wave, and time parameters during systole are used todetermine a proportional estimation of stroke volume.

The proportional estimate of stroke volume for each beat, can bedetermined in a variety of ways, including but not limited to thefollowing:

a. P2−P1

b. √P2

c. √(P2−P1)

d. √(average(P2, P3))

e. √P2×(T3−T1)

f. √(P2−P1)×(T3−T1)

g. √(average(P2,P3))×(T3−T1)

h. √P2×(T3−T2)

i. √(P2−P1)×(T3−T2)

j. √(average(P2,P3))×(T3−T2)

k. dP/dT max value between T1 and T2

l. Integration of P(t)−P1, from T1 to T2.

m. Integration of the first derivative of the pressure waveform,dP(t)/dT, from T1 to T2.

n. Integration of √(P(t)−P1), from T1 to T2.

o. Integration of √dP(t)/dT, from T1 to T2.

Alternatively, for estimates which integrate pressure changes over timeand which have a downstream reference pressure (P1) (l and n) may bereplaced in the equation with a value that gradually increases as thepulmonary vasculature volume increases during filling along the linethat is defined by endpoints P1,T1 and P3,T3, according to the equation;

P(t)_([P1,T1 to P3,T3]) =P1+[(P3−P1)/(T3−T1)]×(t−T1)

Accordingly, the proportional estimate of stroke volume can also beperformed as follows:

p. Integration of P(t)−P(t)_([P1,T1 to P3,T3]) from T1 to T2.

q. Integration of √(P(t)−P(t)_([P1,T1 to P3,T3])), from T1 to T2.

Alternatively, for estimates that integrate pressure changes or thesquare root of pressure changes over time (l, n, p, and q), integrationover the timeframe from T2 to T3 may also be included, with exclusion ofthe portion of the waveform which is attributed to the reflected wave.The reflected portion of the waveform is delineated by the line definedby endpoints P2,T2 and P3,T3, defined by the equation;

P(t)_([P2,T2 to P3,T3]) =P2+[(P3−P2)/(T3−T2)]×(t−T2)

Accordingly, the proportional estimate of stroke volume can also beperformed as follows:

r. Integration of P(t)−P1, from T1 to T2 plus integration ofP(t)_([P2,T2 to P3,T3])−P1 from T2 to T3.

s. Integration of √(P(t)−P1), from T1 to T2 plus integration of√(P(t)_([P2,T2 to P3,T3])−P1) from T2 to T3.

t. Integration of P(t)−P(t)_([P1,T1 to P3,T3]) from T1 to T2 plusintegration of P(t)_([P2,T2 to P3,T3])−P(t)_([P1,T1 to P3,T3]) from T2to T3.

u. Integration of √(P(t)−P(t)_([P1,T1 to P3,T3]), from T)1 to T2 plusintegration of √(P(t)_([P2,T2 to P3,T3])−P(t)_([P1,T1 to P3,T3])) fromT2 to T3.

A proportional estimate of stroke volume (SV_(prop.est)). is determinedas the average of the compiled proportional estimates from at least onecardiac cycle. The duration or number of cardiac cycles for theaveraging window can be configured as appropriate to the application.The minimum average length preferably exceeds the length of at least onerespiratory cycle in order to average variation attributable to therespiratory cycle.

A proportional estimate of cardiac output is determined by multiplyingthe average proportional estimate of stroke volume by the measuredaverage heart rate.

An initial reference cardiac output measurement is performed for methodcalibration, typically during the sensor implantation procedure using aclinically accepted measurement method such as thermodilution, modifiedFick, or Fick. During the same measurement session, one or more wirelesspulmonary arterial pressure waveform readings are collected. An initialpatient specific constant term (A_(o)) is calculated as the ratio of thereference cardiac output measurement and the proportional estimate ofcardiac output determined during the same measurement session. Thisinitial patient specific constant term indirectly determines the effectsof other relevant parameters such as the RV outflow tract crosssectional area (CSA) and the initial characteristic impedance during thecalibration measurements ((Z_(0,i)); A_(o)=CSA×Z₀. This initial patientspecific constant term is used as a calibration factor that ismultiplied by the proportional estimate of cardiac output to produce theinitial estimated cardiac output value;CO_(est_Zo,i).=A_(o)×SV_(prop.est)×HR.

As a corollary to Ohm's law for electrical circuits, the relationshipbetween pressure changes (AP) and flow (Q) is governed by flow impedance(Z); ΔP(t)=Z(t)×Q(t). Thus, the pressure based proportional estimate ofstroke volume and cardiac output is valid only without relevant changesin impedance. This assumption is valid during short term assessments, aswould be the case during an initial calibration reading of, for example,18s length. However, flow impedance may change over longer timeframesbetween readings. For this reason, also accounting for changes inimpedance between readings is expected to yield improved modelperformance.

Flow impedance has frequency and non-frequency dependent components.

The frequency dependent components of impedance are primarily associatedwith reflected, propagated pressure waves which dynamically influencethe relationship between pressure and flow. These frequency dependenteffects are incorporated into the model through the previously presenteduse of the first upslope incisura as the T2 timepoint in the initialstroke volume estimate. For example, more prominent reflected pressurewaves or faster pressure wave propagation associated with increasedpulmonary vascular impedance results in an earlier first upslopeincisura, which reduces the proportional estimate of stroke volume.Conversely, less prominent reflected pressure waves or slower pressurewave propagation associated with reduced pulmonary vascular impedanceresults in a later first upslope incisura, which results in an increasedproportional estimate of stroke volume.

In one example, changes in the non-frequency dependent, characteristicimpedance after initial calibration are incorporated into the model inorder to achieve improved accuracy in the stroke volume and cardiacoutput estimates without need for recalibration over extendedtimeframes.

The physiological basis for the non-frequency dependent impedance changeestimate, hereafter described as characteristic impedance change, ΔZ(t),is presented as follows. The input stroke volume is a bolus injectionthat is introduced into the pulmonary vasculature during a minor portionof the total cardiac cycle, indicated by the timeframe from start ofsystole to the first upslope incisura (T2−T1). Conversely, the outgoingstroke volume leaves the pulmonary vascular through the pulmonarycapillaries throughout the entire cardiac cycle. During the relativelyshort input stroke volume timeframe, a minor portion of the pulmonaryvascular blood volume leaves the pulmonary arterial vasculature throughthe pulmonary capillary beds, approximately (T2−T1)/(Time intervalbetween beats), approximately <10% of the total outgoing stroke volume.Accordingly, changes in resistance have only a minor impact on thecharacteristic impedance during the short T2−T1 timeframe, and thepulmonary vasculature during the T2−T1 timeframe can be fairlyapproximated as a closed system, with the major component ofcharacteristic impedance determined by the pulmonary vascularcompliance, ΔV/ΔP.

With increased mean, systolic, or diastolic average pulmonary arterialpressures, the pulmonary arterial wall strain modulus increases, andcompliance decreases in a predictable manner, due to the mechanicalproperties of the pulmonary vessels. (Pasierski TJ, CHEST 1993). Basedon this relationship, changes in mean, systolic, or diastolic averagepulmonary pressures from baseline to a follow-up measurement can be usedto infer proportional changes in characteristic impedance from baselinevalues.

The relationship between average pulmonary arterial pressure changes andproportional impedance changes was determined heuristically using dataobtained from 54 NYHA Class III Heart Failure patients with 116follow-up sets of reference cardiac output measurements and wirelesspulmonary arterial pressure measurements performed a mean±st. dev.(min., max) of 463±422 (48, 1281) days post implant. The estimatedCardiac Output for follow-up measurements was determined using theinitially determined constant term from baseline (A_(i)), which does notaccount for changing impedance: CO_(est-Zo,i).=A_(o)×SV_(prop.est)×HR.The effect of changing impedance was inferred using a scatter plot ofthe proportional residual error at follow-up, defined as(CO_(est_Zo,i)−CO_(ref))/CO_(est_Zo,i), vs. changes in average pulmonaryarterial pressure from baseline. There was an observed trend of residualerror with respect to mean pressure changes for mean pressure changes inthe provided example. The pattern of residual error as a function ofmean pulmonary arterial pressure change over the threshold value frombaseline to follow-up, ΔmPAP, was characterized using an exponentialregression, with constant term coefficient, B=−0.025, by the followingequation (FIG. 5):

Curve fit for proportional residual error at follow-up=(CO _(est_Zo) −CO_(ref))/CO _(est_Zo)=1−e ^((B×ΔmPAP))=1−e ^((−0.0255×ΔmPAP))

Predicted residual error=CO _(est_Zo) −CO _(ref) =CO _(est_Zo)×(1−e^((−0.025×ΔmPAP)))

In order to incorporate the impedance change effect, the predictedresidual error is subtracted from CO_(est-Zo,i) to produce a CO estimatewith impedance change effects incorporated, CO_(est_Z)(t).

CO _(est_Z(t)) =CO _(est_Zo,i) −CO _(est_Zo,i)×(1−e^((−0.025×(ΔmPAP)))=CO _(est_Zo,i) ×e ^((−0.025×ΔmPAP))

Finally, it should be noted that model coefficients, such as but notlimited to the mean pressure threshold value and exponential curve fitcoefficient (B), can be used to optimize results based on best fit for agiven population or individual patient, using sets of pressure waveformdata and CO reference values measured at more than one time withrelevant CO change between measurements.

FIGS. 6A and 6B show Bland-Altman charts of CO estimate agreement withreference CO measurements performance using pressure data obtained froma CardioMEMS® (Atlanta, Ga.) wireless implantable sensor. FIG. 6A showsconsistent accuracy agreement across the measurement range. FIG. 6Bshows consistent accuracy agreement over extended timeframes.

As described above, provided herein are methods of predicting anoutcome, evaluating progress or improvement, or treating PAH in asubject. Such methods include administering an effective amount of apharmaceutical agent to the subject. Optionally, the pharmaceuticalagents are contained within a pharmaceutical composition.

Provided herein are compositions containing the provided pharmaceuticalagents and a pharmaceutically acceptable carrier described herein. Theherein provided compositions are suitable of administration in vitro orin vivo. By pharmaceutically acceptable carrier is meant a material thatis not biologically or otherwise undesirable, i.e., the material isadministered to a subject without causing undesirable biological effectsor interacting in a deleterious manner with the other components of thepharmaceutical composition in which it is contained. The carrier isselected to minimize degradation of the active ingredient and tominimize adverse side effects in the subject.

Suitable carriers and their formulations are described in Remington: TheScience and Practice of Pharmacy, 21st Edition, David B. Troy, ed.,Lippicott Williams & Wilkins (2005). Typically, an appropriate amount ofa pharmaceutically-acceptable salt is used in the formulation to renderthe formulation isotonic. Examples of the pharmaceutically-acceptablecarriers include, but are not limited to, sterile water, saline,buffered solutions like Ringer's solution, and dextrose solution. The pHof the solution is generally about 5 to about 8 or from about 7 to 7.5.Other carriers include sustained release preparations such assemipermeable matrices of solid hydrophobic polymers containing theimmunogenic polypeptides. Matrices are in the form of shaped articles,e.g., films, liposomes, or microparticles. Certain carriers may be morepreferable depending upon, for instance, the route of administration andconcentration of composition being administered. Carriers are thosesuitable for administration of the agent to humans or other subjects.

The compositions are administered in a number of ways depending onwhether local or systemic treatment is desired, and on the area to betreated. The compositions are administered via any of several routes ofadministration, including topically, orally, parenterally,intravenously, intra-articularly, intraperitoneally, intramuscularly,subcutaneously, intracavity, transdermally, intrahepatically,intracranially, nebulization/inhalation, or by installation viabronchoscopy. Optionally, the composition is administered by oralinhalation, nasal inhalation, or intranasal mucosal administration.Administration of the compositions by inhalant can be through the noseor mouth via delivery by spraying or droplet mechanism, for example, inthe form of an aerosol.

Preparations for parenteral administration include sterile aqueous ornon-aqueous solutions, suspensions, and emulsions. Examples ofnon-aqueous solvents are propylene glycol, polyethylene glycol,vegetable oils such as olive oil, and injectable organic esters such asethyl oleate. Aqueous carriers include water, alcoholic/aqueoussolutions, emulsions or suspensions, including saline and bufferedmedia. Parenteral vehicles include sodium chloride solution, Ringer'sdextrose, dextrose and sodium chloride, lactated Ringer's, or fixedoils. Intravenous vehicles include fluid and nutrient replenishers,electrolyte replenishers (such as those based on Ringer's dextrose), andthe like. Preservatives and other additives are optionally present suchas, for example, antimicrobials, anti-oxidants, chelating agents, andinert gases and the like.

Formulations for topical administration include ointments, lotions,creams, gels, drops, suppositories, sprays, liquids, and powders.Conventional pharmaceutical carriers, aqueous, powder, or oily bases,thickeners and the like are optionally necessary or desirable.

Compositions for oral administration include powders or granules,suspension or solutions in water or non-aqueous media, capsules,sachets, or tables. Thickeners, flavorings, diluents, emulsifiers,dispersing aids or binders are optionally desirable.

According to the methods taught herein, the subject is administered aneffective amount of the agent, or an effective amount, or dosage, ordosage regimen is determined. The terms effective amount and effectivedosage are used interchangeably. The term effective amount is defined asany amount, for example, to produce a desired physiologic response.

Effective amounts and schedules for administering the agent may bedetermined using, for example, PAP and/or CO values and estimates asdescribed herein. The dosage ranges for administration are those largeenough to produce the desired effect in which one or more symptoms ofthe disease or disorder are affected (e.g., reduced or delayed). Thedosage should not be so large as to cause substantial adverse sideeffects, such as unwanted cross-reactions, anaphylactic reactions, andthe like. The dosage may vary with the age, condition, sex, the extentof the disease or disorder, route of administration, or whether otherdrugs are included in the regimen, and can be determined by one of skillin the art. The dosage can be adjusted by the individual physician inthe event of any contraindications. Dosages can vary, and can beadministered in one or more dose administrations daily, for one orseveral days. Guidance can be found in the literature for appropriatedosages for given classes of pharmaceutical products.

In some examples, the effective dosage or amount, or an effective dosageor treatment regimen or protocol is that which lowers or maintains PAPand/or that raises or maintains CO at a desired level. For example, adesired PAP and/or CO level is a level that is expected to have animproved outcome compared to a previous PAP and/or CO level or levels inan individual or from a control determined from a population ofindividuals. Either may be referred to as a standard. Therefore, forexample, an effective dose or amount is optionally that which reduces ormaintains PAP and/or CO at a therapeutic level that is expected toresult in an improved outcome or in one or more reduced or maintainedclinical conditions.

As used herein, the terms treatment, treat, or treating refers to amethod of reducing the effects of a disease or condition or symptom ofthe disease or condition. Thus in the disclosed method, treatment canrefer to a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%reduction in the severity of an established disease or condition orsymptom of the disease or condition. For example, a method for treatinga disease is considered to be a treatment if there is a 10% reduction inone or more symptoms of the disease in a subject as compared to acontrol. Thus, the reduction can be a 10%, 20%, 30%, 40%, 50%, 60%, 70%,80%, 90%, 100%, or any percent reduction in between 10% and 100% ascompared to native or control levels. It is understood that treatmentdoes not necessarily refer to a cure or complete ablation of thedisease, condition, or symptoms of the disease or condition.

Example 1: Evaluation of PAH Treatment Using an Implantable PressureSensor to Monitor PAP

A 53 year old black male presented with PAH. As shown in FIG. 1, thesubject initially presented with a PAP above 30 mm Hg. As further shownin FIG. 1, treatment with Lasix and then Metolaxone reduced PAP in thesubject to below 25 mm Hg. The subject was maintained between about 25mmHg and 10 mm Hg. The reduction and maintenance of PAP indicatedsuccessful treatment of PAH in the subject.

Example 2: Hemodynamic Parameters for Evaluation and Monitoring of PAHUsing an Implantable Pressure Sensor

As shown in FIGS. 2A and B, an implantable pressure sensor, as describedherein, was used to evaluate CO. FIG. 2A indicates measurement of CO issubject having mPAP>25 and a PVR>3. As shown in FIG. 2B, CO was inagreement with PVR across a wide PVR range.

FIG. 3 shows CO agreement with small pressure changes. Small mPAPchanges (<5 mm Hg) were common, occurring for 55 of 96 (57%) of rightheart catheterization subjects. The level of CO agreement for thesepatients was comparable with larger mPAP changes. A one sampleequivalence test was performed to compare the results for the low andhigh pressure change groups. This test demonstrated equivalence to thereference measurements with an equivalence margin of 0.5 L/min.

FIG. 4 shows use of the implantable sensors described herein todetermine changes in CO, TPR and PAP after medication revisions insubjects having PAH. As shown, the estimated CO was shown to rise aftermedication revision, while the TPR and mPAP were reduced. The data showthe progression of PAH in subject following treatment. The data showtrends in mPAP, CO and TPR in a subject with PAH. The data further showthe combined use of mPAP, CO and TPR trends in monitoring a subjecthaving PAH prior and subsequent to administration of a treatment to thesubject.

FIG. 5 shows the estimated Cardiac Output during the follow-upmeasurement was determined using the initially determined constant termfrom baseline (A_(o)), which does not account for changing impedance:CO_(est-Zo,i).=A_(i)×SV_(prop.est)×HR. The effect of changing impedancewas inferred by a scatter plot of the proportional residual error atfollow-up, defined as (CO_(est_Zo,i)−CO_(ref)) CO_(est_Zo,i), relativeto changes in average pulmonary arterial pressure from baseline. Therewas an observable trend of residual error with respect to mean pressurechanges for mean pressure changes over a threshold value, over 25 mm Hgin the provided example. The pattern of residual error as a function ofmean pulmonary arterial pressure change over the threshold value frombaseline to follow-up, ΔmPAP, was characterized using an exponentialregression, with constant term coefficient B=0.03.

FIG. 6 shows Bland-Altman charts of CO estimate agreement with referenceCO measurements performance using pressure data obtained from aCardioMEMS® (Atlanta, Ga.) wireless implantable sensor. The left handchart shows consistent accuracy agreement across the measurement range.The right hand chart shows consistent accuracy agreement over extendedtimeframes.

FIG. 7 illustrates an exemplary system for communicating with a wirelesssensor implanted within a body. The system includes a coupling loop 100,a base unit 102, a display device 104 and an input device 106, such as akeyboard.

The coupling loop is formed from a band of copper. In one embodiment,the loop is eight inches in diameter. The coupling loop includesswitching and filtering circuitry that is enclosed within a shielded box101. The loop charges the sensor and then couples signals from thesensor into the receiver. The antenna can be shielded to attenuatein-band noise and electromagnetic emissions.

Another possible embodiment for a coupling loop includes separate loopsfor energizing and for receiving, although a single loop can be used forboth functions. PIN diode switching inside the loop assembly is used toprovide isolation between the energizing phase and the receive phase byopening the RX path pin diodes during the energizing period, and openingthe energizing path pin diodes during the coupling period. Multipleenergizing loops can be staggered tuned to achieve a wider bandwidth ofmatching between the transmit coils and the transmit circuitry.

The base unit includes an RF amplifier, a receiver, and signalprocessing circuitry.

The display 104 and the input device 106 are used in connection with theuser interface for the system. In the embodiment illustrated in FIG. 7the display device and the input device are connected to the base unit.In this embodiment, the base unit also provides conventional computingfunctions. In other embodiments, the base unit can be connected to aconventional computer, such as a laptop, via a communications link, suchas an RS-232 link. If a separate computer is used, then the displaydevice and the input devices associated with the computer can be used toprovide the user interface. In one embodiment, LABVIEW software is usedto provide the user interface, as well as to provide graphics, store andorganize data and perform calculations for calibration andnormalization. The user interface records and displays patient data andguides the user through surgical and follow-up procedures.

An optional printer 108 is connected to the base unit and can be used toprint out patient data or other types of information. As will beapparent to those skilled in the art other configurations of the system,as well as additional or fewer components can be utilized with theinvention.

Patient and system information can be stored within a removable datastorage unit, such as a portable USB storage device, floppy disk, smartcard, or any other similar device. The patient information can betransferred to the physician's personal computer for analysis, review,or storage. An optional network connection can be provided to automatestorage or data transfer. Once the data is retrieved from the system, acustom or third party source can be employed to assist the physicianwith data analysis or storage.

FIG. 7 illustrates the system communicating with a sensor 120 implantedin a patient. The system is used in two environments: 1) the operatingroom during implant and 2) the doctor's office during follow-upexaminations. During implant the system is used to record at least twomeasurements. The first measurement is taken during introduction of thesensor for calibration and the second measurement is taken afterplacement for functional verification of the stent graft. Themeasurements can be taken by placing the coupling loop either on oradjacent to the patient's back or the patient's stomach for a sensorthat measures properties associated with an abdominal aneurysm. Forother types of measurements, the coupling loop may be placed in otherlocations. For example, to measure properties associated with the heart,the coupling loop can be placed on the patient's back or the patient'schest.

The system communicates with the implanted sensor to determine theresonant frequency of the sensor. As described in more detail in thepatent documents referenced in the Background section, a sensortypically includes an inductive-capacitive (“LC”) resonant circuithaving a variable capacitor. The distance between the plates of thevariable capacitor varies as the surrounding pressure varies. Thus, theresonant frequency of the circuit can be used to determine the pressure.

The system energizes the sensor with an RF burst. The energizing signalis a low duty cycle, gated burst of RF energy of a predeterminedfrequency or set of frequencies and a predetermined amplitude.Typically, the duty cycle of the energizing signal ranges from 0.1% to50%. In one embodiment, the system energizes the sensor with a 30-37.5MHz fundamental signal at a pulse repetition rate of 100 kHz with a dutycycle of 20%. The energizing signal is coupled to the sensor via amagnetic loop. This signal induces a current in the sensor which hasmaximum amplitude at the resonant frequency of the sensor. During thistime, the sensor charges exponentially to a steady-state amplitude thatis proportional to the coupling efficiency, distance between the sensorand loop, and the RF power. The speed at which the sensor charges isdirectly related to the Q (quality factor) of the sensor. Therefore, the“on time” of the pulse repetition duty cycle is optimized for the Q ofthe sensor. The system receives the ring down response of the sensor viamagnetic coupling and determines the resonant frequency of the sensor.When the main unit is coupling energy at or near the resonant frequencyof the sensor, the amplitude of the sensor return is maximized, and thephase of the sensor return will be close to zero degrees with respect tothe energizing phase. The sensor return signal is processed viaphase-locked-loops to steer the frequency and phase of the nextenergizing pulse.

Disclosed are materials, compositions, and components that can be usedfor, can be used in conjunction with, can be used in preparation for, orare products of the disclosed methods and compositions. These and othermaterials are disclosed herein, and it is understood that whencombinations, subsets, interactions, groups, etc. of these materials aredisclosed that while specific reference of each various individual andcollective combinations and permutations of these compounds may not beexplicitly disclosed, each is specifically contemplated and describedherein. For example, if a method is disclosed and discussed and a numberof modifications that can be made to a number of molecules including themethod are discussed, each and every combination and permutation of themethod, and the modifications that are possible are specificallycontemplated unless specifically indicated to the contrary. Likewise,any subset or combination of these is also specifically contemplated anddisclosed. This concept applies to all aspects of this disclosureincluding, but not limited to, steps in methods using the disclosedcompositions. Thus, if there are a variety of additional steps that canbe performed, it is understood that each of these additional steps canbe performed with any specific method steps or combination of methodsteps of the disclosed methods, and that each such combination or subsetof combinations is specifically contemplated and should be considereddisclosed.

Publications cited herein and the material for which they are cited arehereby specifically incorporated by reference in their entireties.

What is claimed is:
 1. A method of evaluating progress of pulmonaryarterial hypertension (PAH) in a subject, or an outcome in the subjecthaving PAH, comprising: obtaining pulmonary artery pressure (PAP) dataover a cardiac cycle from a wireless pressure sensor implanted in apulmonary artery of the subject, the wireless pressure sensor wirelesslycommunicating with a base unit, the base unit communicating with asecond computer; utilizing a processor of at least one of the base unitor second computer for: determining first and second PAP valuesexperienced within the pulmonary artery based on the PAP data;estimating first and second cardiac outputs (COs) based on the first andsecond PAP values experienced within the pulmonary artery over thecardiac cycle; comparing the first and second PAP values and comparingthe first and second COs; monitoring a PAH progression or outcome in thesubject based on the comparing of first and second PAPs and first andsecond COs in connection with determining whether to change at least oneof a pharmaceutical agent, dosage or dosing regimen based on the PAHprogression or outcome in the subject.
 2. The method of claim 1, furthercomprising: communicating the PAP data from the wireless pressure sensorto the base unit, the processor of the base unit performing thedetermining, estimating, and comparing.
 3. The method of claim 1,further comprising: transferring the first and second PAP values and thefirst and second COs from the base unit to the second computer.
 4. Themethod of claim 3, further comprising: communicating the PAP data fromthe wireless pressure sensor to the base unit and to the secondcomputer, the processor of the second computer performing thedetermining, estimating, and comparing.
 5. The method of claim 1,further comprising transferring, from the base unit to the secondcomputer, at least one of the i) first and second PAP values, ii) firstand second COs, or iii) the PAP progression or outcome.
 6. The method ofclaim 1, further comprising maintaining a network connection between thebase unit and second computer.
 7. The method of claim 1, wherein: a. adecrease in the first PAP value compared to the second PAP valuecombined with the first CO estimate having increased or remained stablein comparison to the second CO estimate, or b. the first PAP value beingstable when compared to the second PAP value combined with the first COestimate having increased when compared to the second CO estimate,indicates or predicts improvement of the PAH in the subject.
 8. Themethod of claim 1, wherein the pressure sensor lacks percutaneousconnections.
 9. The method of claim 1, further comprising energizing thepressure sensor from the base unit.
 10. The method of claim 1, furthercomprising maintaining administration of the pharmaceutical agent at itscurrent dosage and/or dosing regimen when improvement is indicated. 11.A system of evaluating progress of pulmonary arterial hypertension (PAH)in a subject, or an outcome in the subject having PAH, comprising: awireless pressure sensor configured to be implanted in a pulmonaryartery of the subject obtain and to obtain pulmonary artery pressure(PAP) data over a cardiac cycle; a base unit configured to wirelesslycommunicate with the pressure sensor; a second computer configured tocommunicate with the base unit; at least one of the base unit or secondcomputer including a processor configured to: determine first and secondPAP values experienced within the pulmonary artery based on the PAPdata; estimate first and second cardiac outputs (COs) based on the firstand second PAP values experienced within the pulmonary artery over thecardiac cycle; compare the first and second PAP values and comparing thefirst and second COs; and monitor a PAH progression or outcome in thesubject based on the comparing of first and second PAPs and first andsecond COs in connection with determining whether to change at least oneof a pharmaceutical agent, dosage or dosing regimen based on the PAHprogression or outcome in the subject.
 12. The system of claim 11,wherein the base unit includes a first processor that is configured toreceive the PAP data from the wireless pressure sensor, determine thefirst and second PAP values, estimate the first and second COs, the baseunit including memory configured to store the first and second PAPvalues and the first and second COs.
 13. The system of claim 11, furthercomprising a network connection configured to transfer the first andsecond PAP values and the first and second COs from the base unit to thesecond computer.
 14. The system of claim 11, wherein the second computerincludes a first processor that is configured to receive the PAP data,determine the first and second PAP values, estimate the first and secondCOs, the second computer including memory configured to store the firstand second PAP values and the first and second COs.
 15. The system ofclaim 11, wherein the base unit is configured to transfer, to the secondcomputer, at least one of the i) first and second PAP values, ii) firstand second COs, or iii) the PAP progression or outcome.
 16. The systemof claim 11, wherein the pressure sensor is a passive sensor energizedto return pressure readings by an electromagnetic field.
 17. The systemof claim 11, wherein the wireless pressure sensor is configured tocollect PAP data that defines a pulmonary artery pressure waveform whilethe subject is exercising.
 18. The system of claim 11, wherein thewireless pressure sensor is configured to collect PAP data that definesa pulmonary artery pressure waveform while the subject is asleep. 19.The system of claim 11, wherein the processor is further configuredautomatically to modify or maintain the administration of thepharmaceutical agent.
 20. The system of claim 11, wherein the processoris further configured to maintain administration of the pharmaceuticalagent at its current dosage and/or dosing regimen when improvement isindicated.